Chirally functionalized alcohols are very important synthetic intermediates, for example for potential enzyme inhibitors for anticancer therapy, such as, for example, protein kinase C inhibitors, or for anti-HIV agents.
For this reason, many experiments have already been undertaken to obtain these compounds from prochiral ketones.
One of the most customary methods for the preparation of optically active xcex1-hydroxy esters is the asymmetric reduction of the corresponding xcex1-keto esters. Thus the asymmetric reduction of prochiral ketones with chiral systems derived from NaBH4, which are obtained by reaction NaBH4 with, for example, monosaccharides or xcex1-amino acid derivatives, in particular L-proline derivatives, has already been more closely investigated. However, this method only produces moderate optical purities, as is known from Bull. Chem. Soc. Jpn., 64, 175-182 (1991). For this reason, other chiral systems derived from NaBH4 were investigated in this reference. Thus ethyl 2-(3,4-isopropylidenedioxyphenyl)-2-oxoacetate was reduced to the corresponding (R)-hydroxy compound using a system obtained by reaction of NaBH4 with (R,R)-tartaric acid, an ee of up to 78% being obtained. In contrast to this, the asymmetric reduction of propiophenone with the reaction product of NaBH4 and (S,S)-tartaric acid afforded (S)-1-phenyl-1-propanol in an optical yield of only 10%.
EP-A1-0 320 096 likewize describes the reduction of prochiral keto esters or ketones by means of NaBH4 and tartaric acid. In the examples, it is shown here that the use of (R,R)-tartaric acid yields the corresponding (R)-hydroxy compounds in an optical yield of only 15 to at most 85%.
In Synthetic Communications, 14(10), 955-959 (1984), the efficiency of the NaBH4/tartaric acid system in the reduction of cyclic ketones was investigated. In the course of this, ketones, such as 2-methyl-, 3-methyl-, 4-methyl- and 4-t-butylcyclohexanone were reduced to the corresponding alcohols, markedly higher proportions of the more stable equatorial alcohols being obtained with the NaBH4/tartaric acid system than with NaBH4 alone. A change in the optical activity of the tartaric acid had no detectable effect on the stereochemical result of the reduction.
Rather, it can be derived from the literature that the stereoselectivity is strongly dependent on the structure of the substrate and that chiral centers present in the substrate, and/or the nature and size of the substituents of the substrate, have a strong influence on the course of the reduction. This is confirmed, for example, by J. Org. Chem. 1999, 64, 2172-2173. In this reference, the stereoselectivity in the reduction of xcex2-hydroxy or xcex2-alkoxy ketones by means of SmI2 was investigated, it being found that it was possible to reduce substituents having the xcex2-hydroxy substituent in high yield and good optical purity, the hydroxyl group to a significant extent determining both the stereoselectivity and the reaction rate. Substrates which had a protected xcex2-hydroxyl group, for example a xcex2-OBn or OTBS group, were almost completely inert in comparison with compounds having the free hydroxyl group. In the case of these substrates, no reduction was achieved. It also follows from J. Org. Chem., Vol. 56, No. 24, 1991 that the size of the substituents has a great influence on the stereoselectivity.
Unexpectedly, it has now been found that xcex1- or xcex2-ketoesters which have a chiral center in the xcex3 position can be reduced with NaBH4 and (D)- or (L)-tartaric acid to the corresponding diastereomeric hydroxy esters in each case in high optical purity and high yield, the chiral center present in the starting compound having no influence on the formation of the diastereomers.
The invention accordingly relates to a process for the stereoselective reduction of chiral xcex1- or xcex2-keto esters, which comprizes reducing xcex1- or xcex2-ketoesters which have a chiral center in the xcex3 position in an inert solvent at temperatures from xe2x88x9280 to +50xc2x0 C. using a reductant obtained by reaction of NaBH4 and (D)- or (L)-tartaric acid to the corresponding diastereomeric hydroxy compounds in each case.
Chiral xcex1- or xcex2-keto esters which have a chiral center in the xcex3 position are reduced in the process according to the invention. Suitable substrates accordingly preferably have an open-chain, optionally branched alkyl or alkenyl chain. The alkyl or alkenyl chain consists here of 4 to 30, preferably 4 to 15, C atoms. In the case of an alkenyl chain, this can have 1 to 3 double bonds. The chain is substituted in position 1 by a carboxylate group. The ester group is derived here from a primary, secondary or tertiary alcohol. Esters of primary alcohols are preferred. These are accordingly C1-C20-, preferably C3-C6-, alkyl esters, such as methyl, ethyl, propyl, butyl, hexyl esters, etc. A keto group is found either in the xcex1 or xcex2 position to the carboxylate, preferably in the xcex1 position. The substrates have a chiral center in the xcex3 position. A protected OH group, for example a t-butyldiphenylsilyloxy group, a trimethylsilyloxy group, a benzyloxy group or another customary protective group, is preferably found as a substituent in the xcex3 position.
Particularly preferred substrates are those which can be prepared from unsaturated cyanohydrins by means of the Blaise reaction. Methyl (4S)-3-oxo-4-tert-butylsilyloxyundec-5-enoate is very particularly preferred.
According to the invention, the corresponding substrate is reduced using a reductant which is obtained by reaction of NaBH4 with (D)- or (L)-tartaric acid.
Depending on which diastereomer of the corresponding hydroxy compound is desired, NaBH4 is reacted here either with (D)- or with (L)-tartaric acid. The preparation of the actual reductant (the sodium acyloxyborohydride derived from (D)- or (L)-tartaric acid) is preferably carried out in situ, as described, for example, in Synthetic Communications, 14(10), 955-959 (1984); Bull. Chem. Soc. Jpn., 64, 175-182 (1991) or J. Chem. Soc. Perkin Trans I, 1827 (1990) etc. Preferably, the corresponding tartaric acid and NaBH4 are suspended here in a suitable inert diluent which preferably also serves as a solvent for the reduction, NaBH4 in turn preferably being added in portions to a solution of the tartaric acid and the suspension thus obtained being heated to reflux temperature for 0.5 to 6 hours. Suitable diluents or solvents are, for example, alcohols, such as, for example, 2-propanol, t-butanol, etc., ethers, such as tetrahydrofuran (THF), dioxane, diethyl ether etc., aromatics, such as benzene, toluene, xylene, etc. or other solvents which are inert under the reaction conditions. Optionally, the above solvents can also be employed as a solvent mixture. THF or 2-propanol is preferably employed. The molar ratio of NaBH4 to (D)- or (L)-tartaric acid is between 1:0.5 to 1:1.5, the molar ratio preferably being 1:1.
Following the warming of the suspension, the mixture is cooled down to xe2x88x9250xc2x0 C., preferably to xe2x88x9230xc2x0 C. and particularly preferably to xe2x88x9220xc2x0 C. A solution of the substrate to be reduced is then introduced into the solution of the reductant thus obtained. Suitable solvents are once again the solvents listed above. Preferably, the same solvent is employed in the in situ preparation of the reductant and in the reduction. Preferably, the substrate solution is added in a number of portions, particularly preferably dropwise, so that the temperature is kept constant at, particularly preferably, xe2x88x9220xc2x0 C.
The reductant is present here in an excess relative to the substrate. A molar ratio of substrate to reductant of 1:2 to 1:6, particularly preferably of approximately 1:4, is preferred. The reaction mixture is stirred in the course of this. After reduction is complete, i.e. depending on the selected substrate after 1 to 60 hours, hydrochloric acid or sulfuric acid, for example, is added to the reaction mixture for the isolation of the corresponding diastereomer, or for the termination of the reaction. Preferably, ethyl acetate or other suitable solvents, and, if appropriate, sodium chloride are additionally added until the saturation point is reached. After phase separation has taken place, the final product is extracted from the organic phase and purified.
By means of the process according to the invention, it is unexpectedly possible by the selection of D- or L-tartaric acid to obtain the corresponding diastereomeric hydroxy compound in high yield and optical purity. In particular, this is particularly advantageous in the reduction of (4S)-methyl-3-oxo-4-tert-butylsilyloxyundec-5-enoate, since using the process according to the invention, depending on whether (D)- or (L)-tartaric acid is employed, either (3R, 4S)- or (3S, 4S)-methyl-3-hydroxy-4-tert-butylsilyloxyundec-5-enoate can specifically be prepared in excellent diastereomeric excess of over 90%. These compounds are valuable intermediates for the preparation of an inhibitor for protein kinase C or for L-AZT (azidothymidine), a potential anti-HIV agent. Accordingly, the invention further relates to the use of methyl (3R, 4S)- or (3S, 4S)-3-hydroxy-4-tertbutylsilyloxyundec-5-enoate prepared according to the invention for the preparation of the corresponding enantiomerically and diastereomerically pure lactones (4R, 5S)-5-hydroxymethyl-4-tetradecanoyltetrahydrofuran-2-one and (4S, 5S)-5-(E-hept-1-enyl)-4-hydroxytetrahydrofuran-2-one, and its further reaction to give the L-AZT intermediate (2R, 4S, 5S)-5-acetoxy-3-azido-2-hydroxymethyloxolane.
The further reaction of (3R, 4S)-methyl-3-hydroxy-4-tert-butylsiloxyundec-5-enoate to give (4R, 5S)-5-hydroxymethyl-4-tetradecanoyltetrahydrofuran-2-one, an inhibitor of protein kinase C, has a total yield of 32%, whereas previously known preparation variants, such as described, for example, in J. Am. Chem. Soc., 1992, 114, 1059-1070, lead to yields of only 8%. The further processing according to the invention additionally needs only 7 stages, whereas previously 14 stages were customary.
The use according to the invention of (3R, 4S)-methyl-3-hydroxy-4-tert-butylsilyloxyundec-5-enoate (A) for the preparation of (4R, 5S)-5-hydroxymethyl-4-tetradecanoyltetrahydrofuran-2-one (E) accordingly comprizes the following steps:
a) reaction with tetrabutylammonium fluoride (TBAF) in a solvent which is inert under the reaction conditions, such as, for example, THF, at 10 to 40xc2x0 C., preferably at 20-30xc2x0 C., and isolation of the intermediate (4R, 5S)-5-(E-hept-1-enyl)-4-hydroxytetrahydrofuran-2-one (C) by extraction, then
b) reaction with a mixture of pyridine and myristoyl chloride in CH2Cl2 at 10 to 40xc2x0 C., preferably at 20-30xc2x0 C., and isolation of the intermediate (4R, 5S)-5-(E-hept-1-enyl)-4-tetradecanoyltetrahydrofuran-2-one (D) by extraction, and subsequently
c) reaction with ozone at xe2x88x9280 to xe2x88x9260xc2x0 C., heating to 10 to 40xc2x0 C., preferably at 20-30xc2x0 C. and isolation of the final product (4R, 5S)-5-hydroxymethyl-4-tetradecanoyltetrahydrofuran-2-one (E) by addition of BH3:Me2S under a rare gas atmosphere, and also of MeOH after 10 to 30 h.
The intermediate compound for L-AZT is obtained by the following steps by the use according to the invention of methyl (3S, 4S)-3-hydroxy-4-tert-butylsilyloxyundec-5-enoate (B):
a) reaction with TBAF in a solvent which is inert under the reaction conditions, such as, for example, THF at 10 to 40xc2x0 C., preferably at 20-30xc2x0 C., and isolation of the intermediate (4S, 5S)-5-(E-hept-1-enyl)-4-hydroxytetrahydrofuran-2-one (F), then
b) reaction with a cooled (0 to 10xc2x0 C., preferably 5xc2x0 C.) solution of imidazole in DMF and t-butyldiphenylsilyl chloride, warming to 10 to 40xc2x0 C., preferably to 20-30xc2x0 C., and isolation of the intermediate (4S,5S)-4-tert-butyldiphenylsiloxy-5-(E-hept-1-enyl)tetrahydrofuran-2-one (G) by extraction, additionally
c) reaction with diisobutylaluminum hydride (DIBAL) under a rare gas atmosphere at xe2x88x9280 to xe2x88x9260xc2x0 C., warming to 10 to 40xc2x0 C., preferably to 20-30xc2x0 C., and isolation of the intermediate (2S, 4S, 5S)-5-acetoxy-3-tert-butyldiphenylsilyloxy-2-(E-hept-1-enyl)oxolane (H) by extraction, additionally
d) reaction of a cooled solution (0 to 10xc2x0 C., preferably 5xc2x0 C.) of (2S, 4S, 5S)-5-acetoxy-3-tert-butyldiphenylsilyloxy-2-(E-hept-1-enyl)oxolane with TBAF, warming to 10 to 40xc2x0 C., preferably to 20-30xc2x0 C., and isolation of the intermediate (2S, 4S, 5S)-5-acetoxy-2-(E-hept-1-enyl)-3-hydroxyoxolane (I) by extraction, and
e) reaction of a cooled solution (0 to 10xc2x0 C., preferably 5xc2x0 C.) of (2S, 4S, 5S)-5-acetoxy-2-(E-hept-1-enyl)-3-hydroxyoxolane with pyridine and with trifluoroacetic anhydride, addition of sodium azide followed by DMF, warming to 10 to 40xc2x0 C., preferably to 20-30xc2x0 C., and isolation of the intermediate (2S, 4S, 5S)-5-acetoxy-3-azido-2-(E-hept-1-enyl)oxolane (J) by extraction and
f) reaction with ozone, reduction analogously to Hoffman, J. Org. Chem. 1997 (62), 2458-2465 or Hudlicky, J. Org. Chem. 1998 (63)510-520 and isolation of the final product (2R, 4S, 5S)-5-acetoxy-3-azido-2hydroxymethyloxolane (K).